The invention relates to novel heterocycles containing aminobenzothiazole and aminobenzoxazole derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions. In particular, the derivatives may be used in pharmaceutical compositions effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis.
Thrombotic complications are a major cause of death in the industrialized world. Examples of these complications include acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura. Thrombotic and restenotic complications also occur following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses. It is generally thought that platelet aggregates play a critical role in these events. Blood platelets, which normally circulate freely in the vasculature, become activated and aggregate to form a thrombus with disturbed blood flow caused by ruptured atherosclerotic lesions or by invasive treatments such as angioplasty, resulting in vascular occlusion. Platelet activation can be initiated by a variety of agents, e.g., exposed subendothelial matrix molecules such as collagen, or by thrombin which is formed in the coagulation cascade.
An important mediator of platelet activation and aggregation is ADP (adenosine 5xe2x80x2-diphosphate) which is released from blood platelets in the vasculature upon activation by various agents, such as collagen and thrombin, and from damaged blood cells, endothelium or tissues. ADP activates platelets through specific platelet ADP receptors, sometimes referred to as P2T receptors (Hourani et al., Trends Pharmacol. Sci. 15, 103 (1994); Savi et al., Med Res. Rev. 16, 159 (1996); Mills, Thromb. Hemost. 76, 835 (1996); Gachet et al., Thromb. Hemost. 78, 271 (1997)). This results in the recruitment of more platelets and stabilization of existing platelet aggregates. Platelet ADP receptors mediating aggregation are activated by ADP and some of its derivatives and antagonized by ATP (adenosine 5xe2x80x2-triphosphate) and some of its derivatives. Therefore, platelet ADP receptors are members of the family of P2 receptors activated by purine and/or pyrimidine nucleotides (Harden et al., Annu. Rev. Pharmacol. Toxicol. 35, 541 (1995); North et al., Curr. Opin. Neurobiol. 7, 346 (1997)). Studies of inherited disorders in humans and rats which result in a reduction of ADP release from platelets or reduced ADP receptor number and signaling confirm the critical role in platelet aggregation of ADP and the ADP receptor itself. Potent inhibitors of ADP-induced platelet aggregation therefore might be useful as antithrombotic drugs.
Various directly or indirectly acting synthetic inhibitors of ADP-dependent platelet aggregation with antithrombotic activity have been reported. The orally active antithrombotic thienopyridines ticlopidine and clopidogrel inhibit ADP-induced platelet aggregation, binding of radiolabeled ADP receptor agonist 2-methylthioadenosine 5xe2x80x2-diphosphate to platelets, and other ADP-dependent events indirectly, probably via formation of an unknown metabolite, in humans or animals (Savi et al., Med. Res. Rev. 16, 159 (1996)). Some derivatives of the endogenous antagonist ATP, e.g., ARL (formerly FPL) 67085, are selective platelet ADP receptor antagonists which inhibit ADP-dependent platelet aggregation and are effective in animal thrombosis models (Mills, Thromb. Hemost. 76, 835 (1996); Humphries et al., Trends Pharmacol. Sci. 16, 179 (1995); WO 92/17488)). Derivatives of P1,P4-diadenosine 5xe2x80x2, 5xe2x80x2xe2x80x3-P1,P4-tetraphosphate have also been reported to both inhibit ADP-dependent platelet aggregation in vitro and thrombosis in animal models (Kim et al., Proc. Natl. Acad. Sci. USA 89, 11056 (1992); Chan et al., Proc. Natl. Acad Sci. USA 94, 4034 (1997); U.S. Pat. No. 5,681,823; WO 89/04321).
Despite these compounds, there exists a need for more effective platelet ADP receptor inhibitors. In particular, there is a need for platelet ADP receptor inhibitors having antithrombotic activity that are useful in the prevention and/or treatment of cardiovascular diseases, particularly those related to thrombosis.
The invention provides compounds of formula (I): 
In another aspect, the invention provides pharmaceutical compositions for preventing or treating thrombosis in a mammal containing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention further provides a method for preventing or treating thrombosis in a mammal by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
1. Definitions
In accordance with the invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term xe2x80x9cC1-C6 alkylxe2x80x9d as used herein refers to a straight or branched hydrocarbon containing one to six carbon atoms.
The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d as used herein refers to a cyclic aliphatic hydrocarbon containing three to eight carbon atoms.
The term xe2x80x9cphenylxe2x80x9d as used herein refers to a six carbon containing aromatic ring which can be variously mono- or poly-substituted with H, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, nitro, fluoro, chloro, bromo, iodo, hydroxycarbonyl, or C1-C6 alkoxycarbonyl.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d as used herein refers to an ether moiety whereby the oxygen is connected to a straight or branched chain of carbon atoms of the number indicated.
The term xe2x80x9cphenoxyxe2x80x9d as used herein refers to an ether moiety whereby the oxygen is connected to a phenyl substituent, the latter being defined as above.
The term xe2x80x9cmono-C1-C6 alkylaminoxe2x80x9d as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one C1-C6 alkyl substituent, the latter being defined as above.
The term xe2x80x9cdi-C1-C6 alkylaminoxe2x80x9d as used herein refers to an amino moiety whereby the nitrogen is substituted with two C1-C6 alkyl substituents as defined above.
The term xe2x80x9cmonoarylaminoxe2x80x9d as used herein refers to an amino moiety whereby the nitrogen is substituted with one H and one aryl substituent, such as a phenyl, the latter being defined as above.
The term xe2x80x9cdiarylaminoxe2x80x9d as used herein refers to an amino moiety whereby the nitrogen is substituted with two aryl substituents, such as phenyl, the latter being defined as above.
The term xe2x80x9cC1-C6 alkylsulfonylxe2x80x9d as used herein refers to a dioxosulfur moiety with the sulfur atom also connected to one C1-C6 alkyl substituent, the latter being defined as above.
The term xe2x80x9cC1-C6 alkoxycarbonylxe2x80x9d as used herein refers to a hydroxycarbonyl moiety whereby the hydrogen is replaced by a C1-C6 alkyl substituent, the latter being defined as above.
The term xe2x80x9cheterocyclic groupxe2x80x9d as used herein refers to any saturated or unsaturated mono- or bicyclic ring system, containing from one to five heteroatoms. Each heteroatom may independently be nitrogen, oxygen or sulfur. Examples of suitable heterocyclic groups include, but are not limited to, piperidyl, pyrrolidinyl, pyridyl, piperazinyl, piperidonyl, thiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridoxazolyl, pyridothiazolyl, pyridazinoxazolyl, pyridazinothiazolyl, pyrimidothiazolyl, pyrimidoxazolyl, pyrazinothiazolyl, pyrazinoxazolyl, triazinothiazolyl, and triazinoxazolyl.
A xe2x80x9cpharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable. The salts may be formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as, but not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic. acid, salicylic acid and the like.
Similarly, xe2x80x9cpharmaceutically acceptable base addition saltsxe2x80x9d include but are not limited to those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum bases, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropyl amine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cBiological propertyxe2x80x9d for the purposes herein means an in vitro or in vivo biological effect or an antigenic function or activity that is directly or indirectly performed by a compound of the invention. Effect or functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, including the aggregation of platelets or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it.
2. Compounds of the Invention
Compounds of formula (I) below represent one embodiment of the invention: 
In formula (I):
W is carbon or nitrogen, wherein at least one W is a carbon;
Y is nitrogen, oxygen, or sulfur;
R1 is, independently, H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, pyridyl, pyrimidinyl, hydroxyl, C1C6 alkoxy, phenoxy, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, monoarylamino, diarylamino, nitro, fluoro, chloro, bromo, iodo, C1-C6 alkylsulfonyl, hydroxycarbonyl, C1-C6 alkoxycarbonyl, absent if W is a nitrogen, or adjacent R1 groups together may form a five- or six-membered alicyclic ring, a six-membered aromatic ring, or a six-membered heteroaromatic ring containing one or two nitrogens, with the proviso that when a sequence of three Wxe2x80x94R1 groups form a N(R1)xe2x80x94C(R1)xe2x80x94N(R1) sequence, the R1 bound to carbon is not a halogen;
R2 and R3 are, independently, H, C1-C6 alkyl, C3-C8 cycloalkyl, or R2 and R3 together form an alicyclic ring containing 3 to 8 carbon atoms; and
R4 is a substituted or unsubstituted heterocyclic group containing at least one heteroatom of nitrogen, oxygen, or sulfur. Suitable substituents of R4 include those groups encompassed by R1.
In a preferred embodiment of a compound of formula (I):
W is carbon or nitrogen, wherein at least one W is a carbon;
Y is oxygen or sulfur;
R1is, independently, H, C1-C6 alkyl, phenyl, pyridyl, pyrimidinyl, C1-C6 alkoxy, phenoxy, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C1-C6 alkylsulfonyl, absent if W is a nitrogen, or adjacent R1 groups together form a six-membered aromatic ring, or a six-membered heteroaromatic ring containing one or two nitrogens, with the proviso that when a sequence of three Wxe2x80x94R1 groups form a N(R1)xe2x80x94C(R1)xe2x80x94N(R1) sequence, the R1 bound to carbon is not a halogen;
R2 and R3 are, independently, H or C1-C6 alkyl; and
R4 is a substituted or unsubstituted heterocyclic group containing at least one heteroatom of nitrogen, oxygen, or sulfur. Suitable substituents of R4 include those groups encompassed by R1 as described herein.
In a more preferred embodiment of a compound of formula (I):
W is carbon;
Y is sulfur;
R1 is, independently, H, pyridyl, pyrimidinyl, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, with the proviso that R1 at the 8-position is C1-C6 alkyl, pyridyl, pyrimidinyl, hydroxyl, C1-C6 alkoxy, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or C1-C6 alkylsulfonyl;
R2 and R3 are each a hydrogen; and
R4 is a substituted or unsubstituted heterocyclic group containing at least one heteroatom of nitrogen, oxygen, or sulfur. Suitable substituents of R4 include those groups encompassed by R1 as described herein.
Examples of suitable substituted or unsubstituted R4 groups of a compound of formula (I) include, but are not limited to, piperidyl, pyrrolidinyl, pyridyl, piperazinyl, piperidonyl, thiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridoxazolyl, pyridothiazolyl, pyridazinoxazolyl, pyridazinothiazolyl, pyrimidothiazolyl, pyrimidoxazolyl, pyrazinothiazolyl, pyrazinoxazolyl, triazinothiazolyl, and triazinoxazolyl. Preferred R4 groups include, but are not limited to, benzothiazolyl, benzoxazolyl, pyrido[2,3-d][1,3]oxazolyl, pyrido[2,3-d][1,3]thiazolyl, pyrido[3,4-d][1,3]oxazolyl, pyrido[3,4-d][1,3]thiazolyl, pyrido[4,3-d][1,3]oxazolyl, pyrido[4,3-d][1,3]thiazolyl, pyrido[3,2-d][1,3]oxazolyl, pyrido[3,2-d][1,3]thiazolyl, pyridazino[3,4-d][1,3]oxazolyl, pyridazino[3,4-d][1,3]thiazolyl, pyridazino[4,5-d][1,3]oxazolyl, pyridazino[4,5-d][1,3]thiazolyl, pyridazino[4,3-d][1,3]oxazolyl, pyridazino[4,3-d][1,3]thiazolyl, pyrimido[5,6-d][1,3]thiazolyl, pyrimido[5,6-d][1,3]oxazolyl, pyrimido[5,4-d][1,3]thiazolyl, pyrimido[5,4-d][1,3]oxazolyl, pyrazino[2,3-d][1,3]thiazolyl, pyrazino[2,3-d][1,3]oxazolyl, [1,2,3]triazino[4,5-d][1,3]thiazolyl, [1,2,3]triazino[4,5-d][1,3]oxazolyl, [1,2,4]triazino[6,5-d][1,3]thiazolyl, [1,2,4]triazino[6,5-d][1,3]oxazolyl, [1,2,4]triazino[5,6-d][1,3]thiazolyl, [1,2,4]triazino[5,6-d][1,3]oxazolyl, [1,2,3]triazino[5,4-d][1,3]thiazolyl, and [1,2,3]triazino[5,4-d][1,3]oxazolyl. These compounds are summarized in Table 1 below:
Another preferred embodiment of the compound of formula (I) is a compound of formula (II): 
In formula (II), W, Y, R1, R2, and R3 are each as defined above.
3. Preparation of Compounds of the Invention
A compounds of formula (I) may be prepared by reacting an aminoazole and chlorosulfonylacetyl chloride in an organic solvent in the presence of a molar excess of a tertiary amine base. Preferably, the molar ratio of aminoazole to chlorosulfonylacetyl ranges from about a 1:1, as shown by Scheme A, to about a 2:1, as shown by Scheme B. 
The aminoazole may be any commercially available aminoazole, including for example, substituted 2-aminobenzothiazole or 2-aminobenzoxazole derivatives. The aminoazole may also be prepared synthetically using techniques known in the art. For example, substituted 2-aminobenzoxazoles may be prepared according to the method outlined in Scheme I, where a substituted o-aminophenol is reacted with cyanogen bromide (Sam et al., Journal of Pharmaceutical Sciences 53, 538 (1964)): 
Similarly, substituted 2-aminobenzothiazoles may be prepared according to the method outlined in Scheme II, where a substituted aniline is reacted with ammonium thiocyanate in the presence of bromine or iodine (Mangold et al., Journal of Medicinal Chemistry 25, 630 (1982); Allen et al., Organic Synthesis Collective 3, 76 (1955)): 
These procedures may also be followed to prepare pyrido-fused and pyrimido-fused aminoazoles by, for example, starting with commercially available materials such as 2-amino-3-hydroxypyridine or 4-aminopyrimidine.
Once prepared, pure aminoazoles may be isolated using typical isolation and purification techniques known in the art, such as solvent-solvent extraction and normal phase chromatography on silica gel. The pure aminoazole compounds may then be reacted in the usual manner as described above with chlorosulfonylacetyl chloride in the presence of a tertiary amine base to produce a compound of formula (I). Any tertiary amine base capable of acting as a neutralizing agent for the HCl generated upon reaction of the aminoazole with chlorosulfonylacetyl chloride may be used. Preferably the tertiary amine base is triethylamine or diisopropylethylamine. Likewise the organic solvent may be any solvent common to the practice of organic chemistry such as, for example, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, and N,N-dimethylformamide. Preferably, the organic solvent is tetrahydrofuran.
Preferred methods for preparing compounds of formula (I) and of formula (II) are outlined in, respectively, Schemes III and IV: 
Compounds of formula (I) may then be isolated using typical isolation and purification techniques known in the art, including, for example, chromatographic and recrystallization methods.
In compounds of formula (I) of the invention, carbon atoms to which four non-identical substituents are bonded are asymmetric. For example, when R2 and R3 are not identical, the carbon atom to which R2 and R3 are attached is then bonded to four non-identical groups and as a result the carbon atom is asymmetric. Accordingly, a compound of formula (I) may exist as enantiomers, diastereomers or a mixture thereof. The enantiomers and diastereomers may be separated by chromatographic or crystallization methods, or by other methods known in the art. The asymmetric carbon atom when present in a compound of formula (I) of the invention, may be in one of two configurations (R or S) and both are within the scope of the invention. The presence of small amounts of the opposing enantiomer or diastereomer in the final purified product does not affect the therapeutic or diagnostic application of such compounds.
According to the invention, compounds of formula (I) may be further treated to form pharmaceutically acceptable salts. Treatment of a compound of the invention with an acid or base may form, respectively, a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt, each as defined above. Various inorganic and organic acids and bases known in the art including those defined herein may be used to effect the conversion to the salt.
The invention also relates to pharmaceutically acceptable isomers, hydrates, and solvates of compounds of formula (I). Compounds of formula (I) may also exist in various isomeric and tautomeric forms including pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers.
This invention also encompasses prodrug derivatives of the compounds of formula (I). The term xe2x80x9cprodrugxe2x80x9d refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of formula (I) of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple, etc., depending on the number of biotransformation steps. required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam (1985); Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif. (1992)). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
4. Pharmaceutical Compositions and Methods of Treatment
A compound of formula (I) or formula (II) according to the invention may be formulated into pharmaceutical compositions. Accordingly, the invention also relates to a pharmaceutical composition for preventing or treating thrombosis in a mammal, particularly those pathological conditions involving platelet aggregation, containing a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, each as described above, and a pharmaceutically acceptable carrier or agent. Preferably, a pharmaceutical composition of the invention contains a compound of formula (I) or formula (II) or a salt thereof in an amount effective to inhibit platelet aggregation, more preferably, ADP-dependent aggregation, in a mammal, in particular, a human. Pharmaceutically acceptable carriers or agents include those known in the art and are described. below.
Pharmaceutical compositions of the invention may be prepared by mixing the compound of formula (I) or formula (II) with a physiologically acceptable carrier or agent. Pharmaceutical compositions of the invention may further include excipients, stabilizers, diluents and the like and may be provided in sustained release or timed release formulations. Acceptable carriers, agents, excipients, stablilizers, diluents and the like for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington""s Pharmaceutical Sciences, Mack Publishing Co., ed. A. R. Gennaro (1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as TWEEN, or polyethyleneglycol.
Methods for preventing or treating thrombosis in a mammal embraced by the invention administer a therapeutically effective amount of a compound of formula (I) or formula (II) alone or as part of a pharmaceutical composition of the invention as described above to a mammal, in particular, a human. Compounds of formula (I) or formula (II) and pharmaceutical compositions of the invention containing a compound of formula (I) or formula (II) of the invention are suitable for use alone or as part of a multi-component treatment regimen for the prevention or treatment of cardiovascular diseases, particularly those related to thrombosis. For example, a compound or pharmaceutical composition of the invention may be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-dependent thrombotic indication, including, but not limited to, acute myocardial infarction, unstable angina, chronic stable angina, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia/eclampsia; deep venous thrombosis, embolism, disseminated intravascular coagulation and thrombotic cytopenic purpura, thrombotic and restenotic complications following invasive procedures, e.g., angioplasty, carotid endarterectomy, post CABG (coronary artery bypass graft) surgery, vascular graft surgery, stent placements and insertion of endovascular devices and protheses.
Compounds and pharmaceutical compositions of the invention may also be used as part of a multi-component treatment regimen in combination with other therapeutic or diagnostic agents in the prevention or treatment of thrombosis in a mammal. In certain preferred embodiments, compounds or pharmaceutical compositions of the invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. Coadministration may also allow for application of reduced doses of the thrombolytic agents and therefore minimize potential hemorrhagic side-effects. Compounds and pharmaceutical compositions of the invention may also act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion.
The compounds and pharmaceutical compositions of the invention may be utilized in vivo, ordinarily in mammals such as primates, (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The biological properties, as defined above, of a compound or a pharmaceutical composition of the invention can be readily characterized by methods that are well known in the art such as, for example, by in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters.
Compounds and pharmaceutical compositions of the invention may be in the form of solutions or suspensions. In the management of thromboticdisorders the compounds or pharmaceutical compositions of the invention may also be in such forms as, for example, tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incorporated into shaped articles. Subjects (typically mammalian) in need of treatment using the compounds or pharmaceutical compositions of the invention may be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compound of formula (I) or formula (II) employed, the specific use for which the compound or pharmaceutical composition is employed, and other factors which those skilled in the medical arts will recognize.
Dosage formulations of compounds of formula (I) or formula (II) or pharmaceutical compositions of the invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in a solid form, preferably in a lyophilized form. While the preferred route of administration is orally, the dosage formulations of compounds of formula (I) or formula (II) or pharmaceutical compositions of the invention may also be administered by injection, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally. A variety of dosage forms may be employed as well including, but not limited to, suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of formula (I) or formula (II) and pharmaceutical compositions of the invention may also be incorporated into shapes and articles such as implants which may employ inert materials such biodegradable polymers or synthetic silicones as, for example, SILASTIC, silicone rubber or other polymers commercially available. The compounds and pharmaceutical compositions of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound or pharmaceutical composition of the invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the bodily fluids. For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect.
The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, i.e., platelet ADP receptor inhibition, will be readily determined by one skilled in the art. Typically, applications of a compound or pharmaceutical composition of the invention are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved. The compounds and compositions of the invention may be administered orally in an effective amount within the dosage range of about 0.01 to 1000 mg/kg in a regimen of single or several divided daily doses. If a pharmaceutically acceptable carrier is used in a pharmaceutical composition of the invention, typically, about 5 to 500 mg of a compound of formula (I) or formula (II) is compounded with a pharmaceutically acceptable carrier as called for by accepted pharmaceutical practice including, but not limited to, a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor, etc. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.
Typical adjuvants which may be incorporated into tablets, capsules and the like include, but are not limited to, binders such as acacia, cornstarch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
The following examples are given to illustrate the invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details set forth in these examples.